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J Am Chem Soc. 2019 Oct 30;141(43):17098-17101. doi: 10.1021/jacs.9b09739. Epub 2019 Oct 16.

Pyonitrins A-D: Chimeric Natural Products Produced by Pseudomonas protegens.

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Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , 240 Longwood Avenue , Boston , Massachusetts 02115 , United States.
Structure Elucidation Group, Process and Analytical Research and Development , Merck & Co., Inc. , 33 Avenue Louis Pasteur , Boston , Massachusetts 02115 , United States.
Pharmaceutical Sciences Division, School of Pharmacy , University of Wisconsin-Madison , Madison , Wisconsin 53705 , United States.
Department of Medicine , University of Wisconsin School of Medicine and Public Health , Madison , Wisconsin 53705 , United States.
Department of Bacteriology , University of Wisconsin-Madison , Madison , Wisconsin 53705 , United States.


Bacterial symbionts frequently provide chemical defenses for their hosts, and such systems can provide discovery pathways to new antifungals and structurally intriguing metabolites. This report describes a small family of naturally occurring small molecules with chimeric structures and a mixed biosynthesis that features an unexpected but key nonenzymatic step. An insect-associated Pseudomonas protegens strain's activity in an in vivo murine candidiasis assay led to the discovery of a family of highly hydrogen-deficient metabolites. Bioactivity- and mass-guided fractionation led to the pyonitrins, highly complex aromatic metabolites in which 10 of the 20 carbons are quaternary, and 7 of them are contiguous. The P. protegens genome revealed that the production of the pyonitrins is the result of a spontaneous reaction between biosynthetic intermediates of two well-studied Pseudomonas metabolites, pyochelin and pyrrolnitrin. The combined discovery of the pyonitrins and identification of the responsible biosynthetic gene clusters revealed an unexpected biosynthetic route that would have prevented the discovery of these metabolites by bioinformatic analysis alone.

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